European Association of Urology Guidelines 2021

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EAU Guidelines on Management of Non-Neurogenic Male Lower Urinary Tract Symptoms (LUTS), incl. Benign Prostatic Obstruction (BPO) S. Gravas (Chair), J.N. Cornu, M. Gacci, C. Gratzke, T.R.W. Herrmann, C. Mamoulakis, M. Rieken, M.J. Speakman, K.A.O. Tikkinen Guidelines Associates: M. Karavitakis, I. Kyriazis, S. Malde, V. Sakalis, R. Umbach

© European Association of Urology 2021

TABLE OF CONTENTS

PAGE

1. INTRODUCTION 1.1 Aim and objectives 1.2 Panel composition 1.3 Available publications 1.4 Publication history

4 4 4 4 4

2.

METHODS 2.1 Introduction 2.2 Review 2.3 Patients to whom the guidelines apply

4 4 5 5

3.

EPIDEMIOLOGY, AETIOLOGY AND PATHOPHYSIOLOGY

5

4. DIAGNOSTIC EVALUATION 4.1 Medical history 4.2 Symptom score questionnaires 4.2.1 The International Prostate Symptom Score (IPSS) 4.2.2 The International Consultation on Incontinence Questionnaire (ICIQ-MLUTS) 4.2.3 Danish Prostate Symptom Score (DAN-PSS) 4.3 Frequency volume charts and bladder diaries 4.4 Physical examination and digital-rectal examination 4.4.1 Digital-rectal examination and prostate size evaluation 4.5 Urinalysis 4.6 Prostate-specific antigen (PSA) 4.6.1 PSA and the prediction of prostatic volume 4.6.2 PSA and the probability of PCa 4.6.3 PSA and the prediction of BPO-related outcomes 4.7 Renal function measurement 4.8 Post-void residual urine 4.9 Uroflowmetry 4.10 Imaging 4.10.1 Upper urinary tract 4.10.2 Prostate 4.10.2.1 Prostate size and shape 4.10.3 Voiding cysto-urethrogram 4.11 Urethrocystoscopy 4.12 Urodynamics 4.12.1 Diagnosing bladder outlet obstruction 4.12.2 Videourodynamics 4.13 Non-invasive tests in diagnosing bladder outlet obstruction in men with LUTS 4.13.1 Prostatic configuration/intravesical prostatic protrusion (IPP) 4.13.2 Bladder/detrusor wall thickness and ultrasound-estimated bladder weight 4.13.3 Non-invasive pressure-flow testing 4.13.4 The diagnostic performance of non-invasive tests in diagnosing bladder outlet obstruction in men with LUTS compared with pressure-flow studies

6 6 7 7 7 7 7 8 8 8 9 9 9 9 9 10 10 11 11 11 11 11 11 12 12 12 13 13 13 14 14

5. DISEASE MANAGEMENT 15 5.1 Conservative treatment 15 5.1.1 Watchful waiting (WW) 16 5.1.2 Behavioural and dietary modifications 16 5.1.3 Practical considerations 16 5.2 Pharmacological treatment 17 5.2.1 α1-Adrenoceptor antagonists (α1-blockers) 17 5.2.2 5α-reductase inhibitors 18 5.2.3 Muscarinic receptor antagonists 19 5.2.4 Beta-3 agonist 20 5.2.5 Phosphodiesterase 5 inhibitors 22 5.2.6 Plant extracts - phytotherapy 23

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5.2.7 Combination therapies 5.2.7.1 α1-blockers + 5α-reductase inhibitors 5.2.7.2 α1-blockers + muscarinic receptor antagonists 5.3 Surgical treatment 5.3.1 Resection of the prostate 5.3.1.1 Monopolar and bipolar transurethral resection of the prostate 5.3.1.2 Holmium laser resection of the prostate 5.3.1.3 Thulium:yttrium-aluminium-garnet laser (Tm:YAG) vaporesection of the prostate Mechanism of action: 5.3.1.4 Transurethral incision of the prostate 5.3.2 Enucleation of the prostate 5.3.2.1 Open prostatectomy 5.3.2.2 Bipolar transurethral enucleation of the prostate (B-TUEP) 5.3.2.3 Holmium laser enucleation of the prostate 5.3.2.4 Thulium:yttrium-aluminium-garnet laser (Tm:YAG) enucleation of the prostate Mechanism of action: 5.3.2.5 Diode laser enucleation of the prostate 5.3.2.6 Enucleation techniques under investigation 5.3.2.6.1 Minimal invasive simple prostatectomy 5.3.2.6.2 532 nm (‘Greenlight’) laser enucleation of the prostate 5.3.3 Vaporisation of the prostate 5.3.3.1 Bipolar transurethral vaporisation of the prostate 5.3.3.2 532 nm (‘Greenlight’) laser vaporisation of the prostate 5.3.3.3 Vaporisation techniques under investigation 5.3.3.3.1 Diode laser vaporisation of the prostate 5.3.4 Alternative ablative techniques 5.3.4.1 Aquablation – image guided robotic waterjet ablation: AquaBeam 5.3.4.2 Prostatic artery embolisation 5.3.4.3 Alternative ablative techniques under investigation 5.3.4.3.1 Convective water vapour energy (WAVE) ablation: The Rezum system 5.3.5 Alternative ablative techniques under investigation 5.3.5.1 Prostatic urethral lift 5.3.5.2 Intra-prostatic injections 5.3.5.3 Non-ablative techniques under investigation 5.3.5.3.1 (i)TIND 5.4 Patient selection 5.5 Management of Nocturia in men with lower urinary tract symptoms 5.5.1 Diagnostic assessment 5.5.2 Medical conditions and sleep disorders Shared Care Pathway 5.5.3 Treatment for Nocturia 5.5.3.1 Antidiuretic therapy 5.5.3.2 Medications to treat LUTD 5.5.3.3 Other medications

42 42 42 43 44 44 44 47 47 47 49 49 50 50

6.

FOLLOW-UP 6.1 Watchful waiting (behavioural) 6.2 Medical treatment 6.3 Surgical treatment

51 51 51 52

7.

REFERENCES

52

8.

CONFLICT OF INTEREST

81

9.

CITATION INFORMATION

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1.

INTRODUCTION

1.1

Aim and objectives

Lower urinary tract symptoms (LUTS) are a common complaint in adult men with a major impact on quality of life (QoL), and have a substantial economic burden. The present Guidelines offer practical evidence-based guidance on the assessment and treatment of men aged 40 years or older with various non-neurogenic benign forms of LUTS. The understanding of the LUT as a functional unit, and the multifactorial aetiology of associated symptoms, means that LUTS now constitute the main focus, rather than the former emphasis on Benign Prostatic Hyperplasia (BPH). The term BPH is now regarded as inappropriate as it is Benign Prostatic Obstruction (BPO) that is treated if the obstruction is a significant cause of a man’s LUTS. It must be emphasised that clinical guidelines present the best evidence available to the experts. However, following guideline recommendations will not necessarily result in the best outcome. Guidelines can never replace clinical expertise when making treatment decisions for individual patients, but rather help to focus decisions - also taking personal values and preferences/individual circumstances of patients into account. Guidelines are not mandates and do not purport to be a legal standard of care.

1.2

Panel composition

The EAU Non-neurogenic Male LUTS Guidelines Panel consists of an international group of experts with urological and clinical epidemiological backgrounds. All experts involved in the production of this document have submitted potential conflict of interest statements which can be viewed on the EAU website Uroweb: http://uroweb.org/guideline/treatment-of-non-neurogenic-male-luts/.

1.3

Available publications

A quick reference document, the Pocket Guidelines, is available in print and as an app for iOS and Android devices. These are abridged versions which may require consultation together with the full text version. All documents are accessible through the EAU website Uroweb: http://www.uroweb.org/guideline/treatment-ofnon-neurogenic-male-luts/.

1.4

Publication history

The Non-neurogenic Male LUTS Guidelines was first published in 2000. The 2021 document presents a limited update of the 2020 publication; the next full update of the Non-neurogenic Male LUTS Guidelines will be presented in 2022.

2.

METHODS

2.1

Introduction

For the 2021 Management of Non-Neurogenic Male LUTS Guidelines, a detailed review and restructuring of section 5.3 Surgical Treatment has been undertaken. Section 5.3 has been restructured to reflect surgical approach rather than specific technologies and is now divided into five sections: resection; enucleation; vaporisation; alternative ablative techniques; and non-ablative techniques. The literature cut-off date for section 5.3 is April 2019. In addition, a broad and comprehensive literature search related to Serenoa repens in section 5.2.5 Plant extracts – phytotherapy was performed covering the timeframe between the search cut-off date of the EU monograph on S. repens [1] and April 2020. A detailed search strategy is available online: http://www. uroweb.org/guideline/treatment-of-non-neurogenic-male-luts/supplementary-material. For each recommendation within the guidelines there is an accompanying online strength rating form, the bases of which is a modified GRADE methodology [2, 3]. Each strength rating form addresses a number of key elements namely: 1. the overall quality of the evidence which exists for the recommendation, references used in this text are graded according to a classification system modified from the Oxford Centre for Evidence-Based Medicine Levels of Evidence [4]; 2. the magnitude of the effect (individual or combined effects); 3. the certainty of the results (precision, consistency, heterogeneity and other statistical or study related factors); 4. the balance between desirable and undesirable outcomes; 5. the impact of patient values and preferences on the intervention; 6. the certainty of those patient values and preferences.

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These key elements are the basis which panels use to define the strength rating of each recommendation. The strength of each recommendation is represented by the words ‘strong’ or ‘weak’ [5]. The strength of each recommendation is determined by the balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including certainty of estimates), and nature and variability of patient values and preferences. Additional information can be found in the general Methodology section of this print, and online at the EAU website; http://www.uroweb.org/guideline/. A list of associations endorsing the EAU Guidelines can also be viewed online at the above address.

2.2

Review

The Non-Neurogenic Male LUTS Guidelines were peer reviewed prior to publication in 2016.

2.3

Patients to whom the guidelines apply

Recommendations apply to men aged 40 years or older who seek professional help for LUTS in various nonneurogenic and non-malignant conditions such as BPO, detrusor overactivity/overactive bladder (OAB), or nocturnal polyuria. Men with other associated factors relevant to LUT disease (e.g. concomitant neurological diseases, young age, prior LUT disease or surgery) usually require a more extensive work-up, which is not covered in these Guidelines, but may include several tests mentioned in the following sections. EAU Guidelines on Neuro-Urology, Urinary Incontinence, Urological Infections, Urolithiasis, or malignant diseases of the LUT have been developed by other EAU Guidelines Panels and are available online: www.uroweb.org/guidelines/.

3.

EPIDEMIOLOGY, AETIOLOGY AND PATHOPHYSIOLOGY

Lower urinary tract symptoms can be divided into storage, voiding and post-micturition symptoms [6], they are prevalent, cause bother and impair QoL [7-10]. An increasing awareness of LUTS and storage symptoms in particular, is warranted to discuss management options that could increase QoL [11]. Lower urinary tract symptoms are strongly associated with ageing [7, 8], associated costs and burden are therefore likely to increase with future demographic changes [8, 12]. Lower urinary tract symptoms are also associated with a number of modifiable risk factors, suggesting potential targets for prevention (e.g. metabolic syndrome) [13]. In addition, men with moderate-to-severe LUTS may have an increased risk of major adverse cardiac events [14]. Most elderly men have at least one LUTS [8]; however, symptoms are often mild or not very bothersome [10, 11, 15]. Lower urinary tract symptoms can progress dynamically: for some individuals LUTS persist and progress over long time periods, and for others they remit [8]. Lower urinary tract symptoms have traditionally been related to bladder outlet obstruction (BOO), most frequently when histological BPH progresses through benign prostatic enlargement (BPE) to BPO [6, 9]. However, increasing numbers of studies have shown that LUTS are often unrelated to the prostate [8, 16]. Bladder dysfunction may also cause LUTS, including detrusor overactivity/OAB, detrusor underactivity/underactive bladder, as well as other structural or functional abnormalities of the urinary tract and its surrounding tissues [16]. Prostatic inflammation also appears to play a role in BPH pathogenesis and progression [17, 18]. In addition, many non-urological conditions also contribute to urinary symptoms, especially nocturia [8]. The definitions of the most common conditions related to male LUTS are presented below: • Acute retention of urine is defined as a painful, palpable or percussible bladder, when the patient is unable to pass any urine [6]. • Chronic retention of urine is defined as a non-painful bladder, which remains palpable or percussible after the patient has passed urine. Such patients may be incontinent [6]. • Bladder outlet obstruction is the generic term for obstruction during voiding and is characterised by increasing detrusor pressure and reduced urine flow rate. It is usually diagnosed by studying the synchronous values of flow-rate and detrusor pressure [6]. • Benign prostatic obstruction is a form of BOO and may be diagnosed when the cause of outlet obstruction is known to be BPE [6]. In the Guidelines the term BPO or BOO is used as reported by the original studies. • Benign prostatic hyperplasia is a term used (and reserved) for the typical histological pattern, which defines the disease.

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•

•

Detrusor overactivity (DO) is a urodynamic observation characterised by involuntary detrusor contractions during the filling phase which may be spontaneous or provoked [6]. Detrusor overactivity is usually associated with overactive bladder syndrome characterised by urinary urgency, with or without urgency urinary incontinence, usually with increased daytime frequency and nocturia, if there is no proven infection or other obvious pathology [19]. Detrusor underactivity (DU) during voiding is characterised by decreased detrusor voiding pressure leading to a reduced urine flow rate. Detrusor underactivity causes underactive bladder syndrome which is characterised by voiding symptoms similar to those caused by BPO [20].

Figure 1 illustrates the potential causes of LUTS. In any man complaining of LUTS, it is common for more than one of these factors to be present. Figure 1: Causes of male LUTS

Overacve bladder/ Detrusor overacvity

Benign prostac obstrucon

Others

Distal ureteric stone

Nocturnal polyuria

Underacve bladder/ Detrusor underacvity

Bladder tumour

LUTS

Chronic Pelvic Pain syndrome

Urethral stricture

Neurogenic bladder dysfuncon

4.

Urinary tract infecon / Inflammaon

Foreign body

DIAGNOSTIC EVALUATION

Tests are useful for diagnosis, monitoring, assessing the risk of disease progression, treatment planning, and the prediction of treatment outcomes. The clinical assessment of patients with LUTS has two main objectives: • to identify the differential diagnoses, since the origin of male LUTS is multifactorial, the relevant EAU Guidelines on the management of applicable conditions should be followed; • to define the clinical profile (including the risk of disease progression) of men with LUTS in order to provide appropriate care.

4.1

Medical history

The importance of assessing the patient’s history is well recognised [21-23]. A medical history aims to identify the potential causes and relevant comorbidities, including medical and neurological diseases. In addition,

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current medication, lifestyle habits, emotional and psychological factors must be reviewed. The Panel recognises the need to discuss LUTS and the therapeutic pathway from the patient’s perspective. This includes reassuring the patient that there is no definite link between LUTS and prostate cancer (PCa) [24, 25]. As part of the urological/surgical history, a self-completed validated symptom questionnaire (see section 4.2) should be obtained to objectify and quantify LUTS. Bladder diaries or frequency volume charts are particularly beneficial when assessing patients with nocturia and/or storage symptoms (see section 4.3). Sexual function should also be assessed, preferably with validated symptom questionnaires such as the International Index for Erectile Function (IIEF) [26]. Summary of evidence A medical history is an integral part of a patient’s medical evaluation. A medical history aims to identify the potential causes of LUTS as well as any relevant comorbidities and to review the patient’s current medication and lifestyle habits. Recommendation Take a complete medical history from men with LUTS.

4.2

LE 4 4

Strength rating Strong

Symptom score questionnaires

All published guidelines for male LUTS recommend using validated symptom score questionnaires [21, 23]. Several questionnaires have been developed which are sensitive to symptom changes and can be used to monitor treatment [27-33]. Symptom scores are helpful in quantifying LUTS and in identifying which type of symptoms are predominant; however, they are not disease-, gender-, or age-specific. A systematic review (SR) evaluating the diagnostic accuracy of individual symptoms and questionnaires, compared with urodynamic studies (the reference standard), for the diagnosis of BOO in males with LUTS found that individual symptoms and questionnaires for diagnosing BOO were not significantly associated with one another [34]. 4.2.1 The International Prostate Symptom Score (IPSS) The IPSS is an eight-item questionnaire, consisting of seven symptom questions and one QoL question [28]. The IPSS score is categorised as ‘asymptomatic’ (0 points), ‘mildly symptomatic’ (1-7 points), ‘moderately symptomatic’ (8-19 points), and ‘severely symptomatic’ (20-35 points). Limitations include lack of assessment of incontinence, post-micturition symptoms, and bother caused by each separate symptom. 4.2.2 The International Consultation on Incontinence Questionnaire (ICIQ-MLUTS) The ICIQ-MLUTS was created from the International Continence Society (ICS) Male questionnaire. It is a widely used and validated patient completed questionnaire including incontinence questions and bother for each symptom [29]. It contains thirteen items, with subscales for nocturia and OAB, and is available in seventeen languages. 4.2.3 Danish Prostate Symptom Score (DAN-PSS) The DAN-PSS [32] is a symptom score used mainly in Denmark and Finland. The DAN-PSS also has questions on incontinence and measures the bother of each individual LUTS. Summary of evidence LE Symptom questionnaires are sensitive to symptom changes. 3 Symptom scores can quantify LUTS and identify which types of symptoms are predominant; however, 3 they are not disease-, gender-, or age-specific. Recommendation Use a validated symptom score questionnaire including bother and quality of life assessment during the assessment of male LUTS and for re-evaluation during and/or after treatment.

4.3

Strength rating Strong

Frequency volume charts and bladder diaries

The recording of volume and time of each void by the patient is referred to as a frequency volume chart (FVC). Inclusion of additional information such as fluid intake, use of pads, activities during recording, or which grades of symptom severity and bladder sensation is termed a bladder diary [6]. Parameters that can be derived from the FVC and bladder diary include: day-time and night-time voiding frequency, total voided volume, the fraction of urine production during the night (nocturnal polyuria index), and volume of individual voids.

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The mean 24-hour urine production is subject to considerable variation. Likewise, circumstantial influence and intra-individual variation cause FVC parameters to fluctuate, though there is comparatively little data [35, 36]. The FVC/bladder diary is particularly relevant in nocturia, where it underpins the categorisation of underlying mechanism(s) [37-39]. The use of FVCs may cause a ‘bladder training effect’ and influence the frequency of nocturnal voids [40]. The duration of the FVC/bladder diary needs to be long enough to avoid sampling errors, but short enough to avoid non-compliance [41]. A SR of the available literature recommended FVCs should continue for three or more days [42]. The ICIQ-Bladder diary (ICIQ-BD) is the only diary that has undergone full validation [43]. Summary of evidence Frequency volume charts and bladder diaries provide real-time documentation of urinary function and reduce recall bias. Three and seven day FVCs provide reliable measurement of urinary symptoms in patients with LUTS.

LE 3 2b

Recommendations Strength rating Use a bladder diary to assess male LUTS with a prominent storage component or nocturia. Strong Tell the patient to complete a bladder diary for at least three days.

4.4

Strong

Physical examination and digital-rectal examination

Physical examination particularly focusing on the suprapubic area, the external genitalia, the perineum and lower limbs should be performed. Urethral discharge, meatal stenosis, phimosis and penile cancer must be excluded. 4.4.1 Digital-rectal examination and prostate size evaluation Digital-rectal examination (DRE) is the simplest way to assess prostate volume, but the correlation to prostate volume is poor. Quality-control procedures for DRE have been described [44]. Transrectal ultrasound (TRUS) is more accurate in determining prostate volume than DRE. Underestimation of prostate volume by DRE increases with increasing TRUS volume, particularly where the volume is > 30 mL [45]. A model of visual aids has been developed to help urologists estimate prostate volume more accurately [46]. One study concluded that DRE was sufficient to discriminate between prostate volumes > or < 50 mL [47]. Summary of evidence Physical examination is an integral part of a patient’s medical evaluation. Digital-rectal examination can be used to assess prostate volume; however, the correlation to actual prostate volume is poor. Recommendation Perform a physical examination including digital rectal examination in the assessment of male LUTS.

4.5

LE 4 3

Strength rating Strong

Urinalysis

Urinalysis (dipstick or sediment) must be included in the primary evaluation of any patient presenting with LUTS to identify conditions, such as urinary tract infections (UTI), microhaematuria and diabetes mellitus. If abnormal findings are detected further tests are recommended according to other EAU Guidelines, e.g. Guidelines on urinary tract cancers and urological infections [48-51]. Urinalysis is recommended in most Guidelines in the primary management of patients with LUTS [52, 53]. There is limited evidence, but general expert consensus suggests that the benefits outweigh the costs [54]. The value of urinary dipstick/microscopy for diagnosing UTI in men with LUTS without acute frequency and dysuria has been questioned [55]. Summary of evidence Urinalysis (dipstick or sediment) may indicate a UTI, proteinuria, haematuria or glycosuria requiring further assessment. The benefits of urinalysis outweigh the costs.

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LE 3 4

MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021

Recommendation Use urinalysis (by dipstick or urinary sediment) in the assessment of male LUTS.

4.6

Strength rating Strong

Prostate-specific antigen (PSA)

4.6.1 PSA and the prediction of prostatic volume Pooled analysis of placebo-controlled trials of men with LUTS and presumed BPO showed that PSA has a good predictive value for assessing prostate volume, with areas under the curve (AUC) of 0.76-0.78 for various prostate volume thresholds (30 mL, 40 mL, and 50 mL). To achieve a specificity of 70%, whilst maintaining a sensitivity between 65-70%, approximate age-specific criteria for detecting men with prostate glands exceeding 40 mL are PSA > 1.6 ng/mL, > 2.0 ng/mL, and > 2.3 ng/mL, for men with BPH in their 50s, 60s, and 70s, respectively [56]. A strong association between PSA and prostate volume was found in a large community-based study in the Netherlands [57]. A PSA threshold value of 1.5 ng/mL could best predict a prostate volume of > 30 mL, with a positive predictive value (PPV) of 78%. The prediction of prostate volume can also be based on total and free PSA. Both PSA forms predict the TRUS prostate volume (± 20%) in > 90% of the cases [58, 59]. 4.6.2 PSA and the probability of PCa The role of PSA in the diagnosis of PCa is presented by the EAU Guidelines on Prostate Cancer [60]. The potential benefits and harms of using serum PSA testing to diagnose PCa in men with LUTS should be discussed with the patient. 4.6.3 PSA and the prediction of BPO-related outcomes Serum PSA is a stronger predictor of prostate growth than prostate volume [61]. In addition, the PLESS study showed that PSA also predicted the changes in symptoms, QoL/bother, and maximum flow-rate (Qmax) [62]. In a longitudinal study of men managed conservatively, PSA was a highly significant predictor of clinical progression [63, 64]. In the placebo arms of large double-blind studies, baseline serum PSA predicted the risk of acute urinary retention (AUR) and BPO-related surgery [65, 66]. An equivalent link was also confirmed by the Olmsted County Study. The risk for treatment was higher in men with a baseline PSA of > 1.4 ng/mL [67]. Patients with BPO seem to have a higher PSA level and larger prostate volumes. The PPV of PSA for the detection of BPO was recently shown to be 68% [68]. Furthermore, in an epidemiological study, elevated free PSA levels could predict clinical BPH, independent of total PSA levels [69]. Summary of evidence Prostate-specific antigen has a good predictive value for assessing prostate volume and is a strong predictor of prostate growth. Baseline PSA can predict the risk of AUR and BPO-related surgery. Recommendations Measure prostate-specific antigen (PSA) if a diagnosis of prostate cancer will change management. Measure PSA if it assists in the treatment and/or decision making process.

4.7

LE 1b 1b

Strength rating Strong Strong

Renal function measurement

Renal function may be assessed by serum creatinine or estimated glomerular filtration rate (eGFR). Hydronephrosis, renal insufficiency or urinary retention are more prevalent in patients with signs or symptoms of BPO [70]. Even though BPO may be responsible for these complications, there is no conclusive evidence on the mechanism [71]. One study reported that 11% of men with LUTS had renal insufficiency [70]. Neither symptom score nor QoL was associated with the serum creatinine level. Diabetes mellitus or hypertension were the most likely causes of the elevated creatinine concentration. Comiter et al. [72] reported that non-neurogenic voiding dysfunction is not a risk factor for elevated creatinine levels. Koch et al. [73] concluded that only those with an elevated creatinine level require investigational ultrasound (US) of the kidney. In the Olmsted County Study community-dwelling men there was a cross-sectional association between signs and symptoms of BPO (though not prostate volume) and chronic kidney disease (CKD) [74]. In 2,741 consecutive patients who presented with LUTS, decreased Qmax, a history of hypertension and/or diabetes were associated with CKD [75]. Another study demonstrated a correlation between Qmax and eGFR in middle-aged men with moderate-to-severe LUTS [76]. Patients with renal insufficiency are at an increased risk of developing post-operative complications [77].

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Summary of evidence Decreased Qmax and a history of hypertension and/or diabetes are associated with CKD in patients who present with LUTS. Patients with renal insufficiency are at an increased risk of developing post-operative complications. Recommendation Assess renal function if renal impairment is suspected based on history and clinical examination, or in the presence of hydronephrosis, or when considering surgical treatment for male LUTS.

4.8

LE 3 3

Strength rating Strong

Post-void residual urine

Post-void residual (PVR) urine can be assessed by transabdominal US, bladder scan or catheterisation. Post-void residual is not necessarily associated with BOO, since high PVR volumes can be a consequence of obstruction and/or poor detrusor function (DU) [78, 79]. Using a PVR threshold of 50 mL, the diagnostic accuracy of PVR measurement has a PPV of 63% and a negative predictive value (NPV) of 52% for the prediction of BOO [80]. A large PVR is not a contraindication to watchful waiting (WW) or medical therapy, although it may indicate a poor response to treatment and especially to WW. In both the MTOPS and ALTESS studies, a high baseline PVR was associated with an increased risk of symptom progression [65, 66]. Monitoring of changes in PVR over time may allow for identification of patients at risk of AUR [81]. This is of particular importance for the treatment of patients using antimuscarinic medication. In contrast, baseline PVR has little prognostic value for the risk of BPO-related invasive therapy in patients on α1-blockers or WW [82]. However, due to large test-retest variability and lack of outcome studies, no PVR threshold for treatment decision has yet been established; this is a research priority. Summary of evidence The diagnostic accuracy of PVR measurement, using a PVR threshold of 50 mL, has a PPV of 63% and a NPV of 52% for the prediction of BOO. Monitoring of changes in PVR over time may allow for identification of patients at risk of AUR. Recommendation Measure post-void residual in the assessment of male LUTS.

4.9

LE 3 3

Strength rating Weak

Uroflowmetry

Urinary flow rate assessment is a widely used non-invasive urodynamic test. Key parameters are Qmax and flow pattern. Uroflowmetry parameters should preferably be evaluated with voided volume > 150 mL. As Qmax is prone to within-subject variation [83, 84], it is useful to repeat uroflowmetry measurements, especially if the voided volume is < 150 mL, or Qmax or flow pattern is abnormal. The diagnostic accuracy of uroflowmetry for detecting BOO varies considerably and is substantially influenced by threshold values. A threshold Qmax of 10 mL/s has a specificity of 70%, a PPV of 70% and a sensitivity of 47% for BOO. The specificity using a threshold Qmax of 15 mL/s was 38%, the PPV 67% and the sensitivity 82% [85]. If Qmax is > 15 mL/s, physiological compensatory processes mean that BOO cannot be excluded. Low Qmax can arise as a consequence of BOO [86], DUA or an under-filled bladder [87]. Therefore, it is limited as a diagnostic test as it is unable to discriminate between the underlying mechanisms. Specificity can be improved by repeated flow rate testing. Uroflowmetry can be used for monitoring treatment outcomes [88] and correlating symptoms with objective findings. Summary of evidence The diagnostic accuracy of uroflowmetry for detecting BOO varies considerably and is substantially influenced by threshold values. Specificity can be improved by repeated flow rate testing.

LE 2b

Recommendations Perform uroflowmetry in the initial assessment of male LUTS.

Strength rating Weak

Perform uroflowmetry prior to medical or invasive treatment.

Strong

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4.10

Imaging

4.10.1 Upper urinary tract Men with LUTS are not at increased risk for upper tract malignancy or other abnormalities when compared to the overall population [73, 89-91]. Several arguments support the use of renal US in preference to intravenous urography. Ultrasound allows for better characterisation of renal masses, the possibility of investigating the liver and retroperitoneum, and simultaneous evaluation of the bladder, PVR and prostate, together with a lower cost, radiation dose and less side effects [89]. Ultrasound can be used for the evaluation of men with large PVR, haematuria, or a history of urolithiasis. Summary of evidence Men with LUTS are not at increased risk for upper tract malignancy or other abnormalities when compared to the overall population. Ultrasound can be used for the evaluation of men with large PVR, haematuria, or a history of urolithiasis. Recommendation Perform ultrasound of the upper urinary tract in men with LUTS.

LE 3 4

Strength rating Weak

4.10.2 Prostate Imaging of the prostate can be performed by transabdominal US, TRUS, computed tomography (CT), and magnetic resonance imaging (MRI). However, in daily practice, prostate imaging is performed by transabdominal (suprapubic) US or TRUS [89]. 4.10.2.1 Prostate size and shape Assessment of prostate size is important for the selection of interventional treatment, i.e. open prostatectomy (OP), enucleation techniques, transurethral resection, transurethral incision of the prostate (TUIP), or minimally invasive therapies. It is also important prior to treatment with 5α-reductase inhibitors (5-ARIs). Prostate volume predicts symptom progression and the risk of complications [91]. Transrectal US is superior to transabdominal volume measurement [92, 93]. The presence of a median lobe may guide treatment choice in patients scheduled for a minimally invasive approach since medial lobe presence can be a contraindication for some minimally invasive treatments (see section 5.3). Summary of evidence Assessment of prostate size by TRUS or transabdominal US is important for the selection of interventional treatment and prior to treatment with 5-ARIs. Recommendations Perform imaging of the prostate when considering medical treatment for male LUTS, if it assists in the choice of the appropriate drug. Perform imaging of the prostate when considering surgical treatment.

LE 3

Strength rating Weak Strong

4.10.3 Voiding cysto-urethrogram Voiding cysto-urethrogram (VCUG) is not recommended in the routine diagnostic work-up of men with LUTS, but it may be useful for the detection of vesico-ureteral reflux, bladder diverticula, or urethral pathologies. Retrograde urethrography may additionally be useful for the evaluation of suspected urethral strictures.

4.11

Urethrocystoscopy

Patients with a history of microscopic or gross haematuria, urethral stricture, or bladder cancer, who present with LUTS, should undergo urethrocystoscopy during diagnostic evaluation. The evaluation of a prostatic middle lobe with urethrocystocopy should be performed when considering interventional treatments for which the presence of middle lobe is a contraindication. A prospective study evaluated 122 patients with LUTS using uroflowmetry and urethrocystoscopy [94]. The pre-operative Qmax was normal in 25% of 60 patients who had no bladder trabeculation, 21% of 73 patients with mild trabeculation and 12% of 40 patients with marked trabeculation on cystoscopy. All 21 patients who presented with diverticula had a reduced Qmax. Another study showed that there was no significant correlation between the degree of bladder trabeculation (graded from I to IV), and the pre-operative Qmax value in 39 symptomatic men aged 53-83 years [95]. The largest study published on this issue examined the relation of urethroscopic findings to urodynamic

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studies in 492 elderly men with LUTS [96]. The authors noted a correlation between cystoscopic appearance (grade of bladder trabeculation and urethral occlusion) and urodynamic indices, DO and low compliance. It should be noted, however, that BOO was present in 15% of patients with normal cystoscopic findings, while 8% of patients had no obstruction, even in the presence of severe trabeculation [96]. Summary of evidence Patients with a history of microscopic or gross haematuria, urethral stricture, or bladder cancer, who present with LUTS, should undergo urethrocystoscopy during diagnostic evaluation. None of the studies identified a strong association between the urethrocystoscopic and urodynamic findings. Recommendation Perform urethrocystoscopy in men with LUTS prior to minimally invasive/surgical therapies if the findings may change treatment.

4.12

LE 3 3

Strength rating Weak

Urodynamics

In male LUTS, the most widespread invasive urodynamic techniques employed are filling cystometry and pressure flow studies (PFS). The major goal of urodynamics is to explore the functional mechanisms of LUTS, to identify risk factors for adverse outcomes and to provide information for shared decision-making. Most terms and conditions (e.g. DO, low compliance, BOO/BPO, DUA) are defined by urodynamic investigation. 4.12.1 Diagnosing bladder outlet obstruction Pressure flow studies (PFS) are used to diagnose and define the severity of BOO, which is characterised by increased detrusor pressure and decreased urinary flow rate during voiding. Bladder outlet obstruction/BPO has to be differentiated from DUA, which exhibits decreased detrusor pressure during voiding in combination with decreased urinary flow rate [6]. Urodynamic testing may also identify DO. Studies have described an association between BOO and DO [97, 98]. In men with LUTS attributed to BPO, DO was present in 61% and independently associated with BOO grade and ageing [97]. The prevalence of DUA in men with LUTS is 11-40% [99, 100]. Detrusor contractility does not appear to decline in long-term BOO and surgical relief of BOO does not improve contractility [101, 102]. There are no published RCTs in men with LUTS and possible BPO that compare the standard practice investigation (uroflowmetry and PVR measurement) with PFS with respect to the outcome of treatment; however, a study has been completed in the UK, but the final results have not yet been published [103, 104]. Once available they will be included in the next edition of the Guidelines. A Cochrane meta-analysis was done to determine whether performing invasive urodynamic investigation reduces the number of men with continuing symptoms of voiding dysfunction. Two trials with 350 patients were included. Invasive urodynamic testing changed clinical decision making. Patients who underwent urodynamics were less likely to undergo surgery; however, no evidence was found to demonstrate whether this led to reduced symptoms of voiding dysfunction after treatment [105]. A more recent meta-analysis of retrospective studies showed that pre-operative urodynamic DOA has no diagnostic role in the prediction of surgical outcomes in patients with male BOO [106]. Due to the invasive nature of the test, a urodynamic investigation is generally only offered if conservative treatment has failed. The Guidelines Panel attempted to identify specific indications for PFS based on age, findings from other diagnostic tests and previous treatments. The Panel allocated a different degree of obligation for PFS in men > 80 years and men < 50 years, which reflects the lack of evidence. In addition, there was no consensus whether PFS should or may be performed when considering surgery in men with bothersome predominantly voiding LUTS and Qmax > 10 mL/s, although the Panel recognised that with a Qmax < 10 mL/s, BOO is likely and PFS is not necessarily needed. Patients with neurological disease, including those with previous radical pelvic surgery, should be assessed according to the EAU Guidelines on Neuro-Urology [107]. 4.12.2 Videourodynamics Videourodynamics provides additional anatomical and functional information and may be recommended if the clinician considers this is needed to understand the pathophysiological mechanism of an individual patient’s LUTS.

12

MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021

Summary of evidence Within the literature cut-off dates of the 2021 edition of the Guidelines there were no RCTs in men with LUTS and possible BPO that compare the standard practice investigation (uroflowmetry and PVR measurement) with PFS with respect to the outcome of treatment. All subsequent RCTs will be evaluated for inclusion in the next edition of the Guidelines. Recommendations

LE 3

Strength rating

Perform pressure-flow studies (PFS) only in individual patients for specific indications prior Weak to invasive treatment or when further evaluation of the underlying pathophysiology of LUTS is warranted. Perform PFS in men who have had previous unsuccessful (invasive) treatment for LUTS. Weak Perform PFS in men considering invasive treatment who cannot void > 150 mL.

Weak

Perform PFS when considering surgery in men with bothersome predominantly voiding LUTS and Qmax > 10 mL/s. Perform PFS when considering invasive therapy in men with bothersome, predominantly voiding LUTS with a post void residual > 300 mL. Perform PFS when considering invasive treatment in men with bothersome, predominantly voiding LUTS aged > 80 years. Perform PFS when considering invasive treatment in men with bothersome, predominantly voiding LUTS aged < 50 years.

Weak

4.13

Weak Weak Weak

Non-invasive tests in diagnosing bladder outlet obstruction in men with LUTS

4.13.1 Prostatic configuration/intravesical prostatic protrusion (IPP) Prostatic configuration can be evaluated with TRUS, using the concept of the presumed circle area ratio (PCAR) [108]. The PCAR evaluates how closely the transverse US image of the prostate approaches a circular shape. The ratio tends toward one as the prostate becomes more circular. The sensitivity of PCAR was 77% for diagnosing BPO when PCAR was > 0.8, with 75% specificity [108]. Ultrasound measurement of IPP assesses the distance between the tip of the prostate median lobe and bladder neck in the midsagittal plane, using a suprapubically positioned US scanner, with a bladder volume of 150-250 mL; grade I protrusion is 0-4.9 mm, grade II is 5-10 mm and grade III is > 10 mm. Intravesical prostatic protrusion correlates well with BPO (presence and severity) on urodynamic testing, with a PPV of 94% and a NPV of 79% [109]. Intravesical prostatic protrusion may also correlate with prostate volume, DO, bladder compliance, detrusor pressure at maximum urinary flow, BOO index and PVR, and negatively correlates with Qmax [110]. Furthermore, IPP also appears to successfully predict the outcome of a trial without catheter after AUR [111, 112]. However, no information with regard to intra- or inter-observer variability and learning curve is yet available. Therefore, whilst IPP may be a feasible option to infer BPO in men with LUTS, the role of IPP as a non-invasive alternative to PFS in the assessment of male LUTS remains under evaluation. 4.13.2 Bladder/detrusor wall thickness and ultrasound-estimated bladder weight For bladder wall thickness (BWT) assessment, the distance between the mucosa and the adventitia is measured. For detrusor wall thickness (DWT) assessment, the only measurement needed is the detrusor sandwiched between the mucosa and adventitia [113]. A correlation between BWT and PFS parameters has been reported. A threshold value of 5 mm at the anterior bladder wall with a bladder filling of 150 mL was best at differentiating between patients with or without BOO [114]. Detrusor wall thickness at the anterior bladder wall with a bladder filling > 250 mL (threshold value for BOO > 2 mm) has a PPV of 94% and a specificity of 95%, achieving 89% agreement with PFS [73]. Threshold values of 2.0, 2.5, or 2.9 mm for DWT in patients with LUTS are able to identify 81%, 89%, and 100% of patients with BOO, respectively [115]. All studies found that BWT or DWT measurements have a higher diagnostic accuracy for detecting BOO than Qmax or Qave of free uroflowmetry, measurements of PVR, prostate volume, or symptom severity. One study could not demonstrate any difference in BWT between patients with normal urodynamics, BOO or DO. However, the study did not use a specific bladder filling volume for measuring BWT [116]. Disadvantages of the method include the lack of standardisation, and lack of evidence to indicate which measurement (BWT/DWT) is preferable [117]. Measurement of BWT/DWT is therefore not recommended for the diagnostic work-up of men with LUTS. Ultrasound-estimated bladder weight (UEBW) may identify BOO with a diagnostic accuracy of 86% at a cut-off value of 35 g [118, 119]. Severe LUTS and a high UEBW (> 35 g) are risk factors for prostate/BPH surgery in men on α-blockers [120].

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4.13.3 Non-invasive pressure-flow testing The penile cuff method, in which flow is interrupted to estimate isovolumetric bladder pressure, shows promising data, with good test repeatability [121] and interobserver agreement [122]. A nomogram has also been derived [123] whilst a method in which flow is not interrupted is also under investigation [124]. The data generated with the external condom method [125] correlates with invasive PFS in a high proportion of patients [126]. Resistive index [127] and prostatic urethral angle [128] have also been proposed, but are still experimental. The diagnostic performance of non-invasive tests in diagnosing bladder outlet obstruction in men with LUTS compared with pressure-flow studies The diagnostic performance of non-invasive tests in diagnosing BOO in men with LUTS compared with PFS has been investigated in a SR [129]. A total of 42 studies were included is this review. The majority were prospective cohort studies, and the diagnostic accuracy of the following non-invasive tests were assessed: penile cuff test; uroflowmetry; detrusor/bladder wall thickness; bladder weight; external condom catheter method; IPP; Doppler US; prostate volume/height; and near-infrared spectroscopy. Overall, although the majority of studies have a low risk of bias, data regarding the diagnostic accuracy of these non-invasive tests is limited by the heterogeneity of the studies in terms of the threshold values used to define BOO, the different urodynamic definitions of BOO used across different studies and the small number of studies for each test. It was found that specificity, sensitivity, PPV and NPV of the non-invasive tests were highly variable. Therefore, even though several tests have shown promising results regarding non-invasive diagnosis of BOO, invasive urodynamics remains the modality of choice. 4.13.4

Summary of evidence Data regarding the diagnostic accuracy of non-invasive tests is limited by the heterogeneity of the studies as well as the small number of studies for each test. Specificity, sensitivity, PPV and NPV of the non-invasive tests were highly variable. Recommendation Do not offer non-invasive tests as an alternative to pressure-flow studies for diagnosing bladder outlet obstruction in men.

14

LE 1a 1a

Strength rating Strong

MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS (LUTS) - UPDATE MARCH 2021

Figure 2: Assessment algorithm of LUTS in men aged 40 years or older Readers are strongly recommended to read the full text that highlights the current position of each test in detail.

Male LUTS

History (+ sexual function) Symptom score questionnaire Urinalysis Physical examination PSA (if diagnosis of PCa will change the management – discuss with patient) Measurement of PVR

Abnormal DRE Suspicion of neurological disease High PSA Abnormal urinalysis

Evaluate according to relevant guidelines or clinical standard

Treat underlying condition (if any, otherwise return to initial assessment)

Manage according to EAU mLUTS treatment algorithm

No

Bothersome symptoms

Yes Significant PVR

US of kidneys +/- Renal function assessment

FVC in cases of predominant storage LUTS/nocturia US assessment of prostate Uroflowmetry

Medical treatment according to treatment algorithm

Benign conditions of bladder and/or prostate with baseline values PLAN TREATMENT

Endoscopy (if test would alter the choice of surgical modality) Pressure flow studies (see text for specific indications)

Surgical treatment according to treatment algorithm DRE = digital-rectal examination; FVC = frequency volume chart; LUTS = lower urinary tract symptoms; PCa = prostate cancer; PSA = prostate specific antigen; PVR = post-void residual; US = ultrasound.

5.

DISEASE MANAGEMENT

5.1

Conservative treatment

5.1.1 Watchful waiting (WW) Many men with LUTS are not troubled enough by their symptoms to need drug treatment or surgical intervention. All men with LUTS should be formally assessed prior to any allocation of treatment in order to establish symptom severity and to differentiate between men with uncomplicated (the majority) and

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complicated LUTS. Watchful waiting is a viable option for many men with non-bothersome LUTS as few will progress to AUR and complications (e.g. renal insufficiency or stones) [130, 131], whilst others can remain stable for years [132]. In one study, approximately 85% of men with mild LUTS were stable on WW at one year [133]. A study comparing WW and transurethral resection of the prostate (TURP) in men with moderate LUTS showed the surgical group had improved bladder function (flow rates and PVR volumes), especially in those with high levels of bother; 36% of WW patients crossed over to surgery within five years, leaving 64% doing well in the WW group [134, 135]. Increasing symptom bother and PVR volumes are the strongest predictors of WW failure. Men with mild-to-moderate uncomplicated LUTS who are not too troubled by their symptoms are suitable for WW. 5.1.2 Behavioural and dietary modifications It is customary for this type of management to include the following components: • education (about the patient’s condition); • reassurance (that cancer is not a cause of the urinary symptoms); • periodic monitoring; • lifestyle advice [132, 133, 136, 137] such as:: oo reduction of fluid intake at specific times aimed at reducing urinary frequency when most inconvenient (e.g. at night or when going out in public); oo avoidance/moderation of intake of caffeine or alcohol, which may have a diuretic and irritant effect, thereby increasing fluid output and enhancing frequency, urgency and nocturia; oo use of relaxed and double-voiding techniques; oo urethral milking to prevent post-micturition dribble; oo distraction techniques such as penile squeeze, breathing exercises, perineal pressure, and mental tricks to take the mind off the bladder and toilet, to help control OAB symptoms; oo bladder retraining that encourages men to hold on when they have urgency to increase their bladder capacity and the time between voids; oo reviewing the medication and optimising the time of administration or substituting drugs for others that have fewer urinary effects (these recommendations apply especially to diuretics); oo providing necessary assistance when there is impairment of dexterity, mobility, or mental state; oo treatment of constipation. There now exists evidence that self-management as part of WW reduces both symptoms and progression [136, 137]. Men randomised to three self-care management sessions in addition to standard care had better symptom improvement and QoL than men treated with standard care only, for up to a year [136]. 5.1.3 Practical considerations The components of self-care management have not been individually studied. The above components of lifestyle advice have been derived from formal consensus methodology [138]. Further research in this area is required. Summary of evidence Watchful waiting is usually a safe alternative for men who are less bothered by urinary difficulty or who wish to delay treatment